In nano-scale liquid chromatography, it is generally desirable to achieve a low rate of elution of analytes. Although normal-scale High Performance Liquid Chromatography (HPLC) is performed with mobile phase flow rates of about 0.1 to 5.0 mL/min and micro-scale HPLC is performed with mobile phase flow rates of about 1 to 100 μL/min, nano-scale HPLC requires mobile phase flow rates approximately in the 50-1000 mL/min range. Generally, pumps used in nano-scale chromatography require sensitive and accurate flow rate information for control and monitoring purposes.
Fluid flow rates can be determined by measuring the thermal energy in the fluid. Many HPLCs employ thermal flow sensors to monitor flow rates.
The physical principle underlying some of these thermal sensors is the thermoelectric effect, and is also commonly known as the Seebeck effect. The Seebeck effect provides that a conductor subjected to a thermal gradient will develop a proportional electrical potential gradient. The magnitude of the electrical potential depends on a Seebeck coefficient of the conductor, which is an intrinsic property of the conductor. For example, if points A and B on a wire conductor are held at different temperatures TA and TB, then an electrical potential E is created between points A and B and the magnitude of the electrical potential depends upon the Seebeck coefficient of the wire material.
A thermocouple is a conventional device for measuring thermoelectric effects, and FIG. 2A depicts a typical thermocouple configured to sense thermal energy. Materials A and B are subjected to a temperature gradient measured as two different temperatures T1 and T2. The resulting electrical potential V is the product of the differences between the Seebeck coefficients SA and SB and the differences between the temperatures T1 and T2, as illustrated by the equation below:V=(SB−SA)(T2−T1)
If the Seebeck coefficients of materials A and B are known, and T1 is held at a known temperature, the temperature T2 can be determined by solving the above equation for T2, or:T2=T1+V/(SB−SA)
Therefore, the temperature T2 can be calculated by measuring the voltage V and holding T1 at some known temperature. Furthermore, commonly used thermocouple materials have stable, linear, and well-understood thermoelectric properties for a defined temperature range. Accurate temperature measurements can be made using conventional thermocouple materials. For Example, type-K thermocouples constructed with Chromel and Alumel are the most commonly used thermocouples. Type-N thermocouples constructed with Nicrosil and Nisil are commonly used for high-temperature application. Type-E thermocouples constructed with Chromel and Constantan are commonly used for cryogenic applications. These thermocouple materials are also relatively inert and can be used to make direct temperature measurements in a wide variety of environments.
However, existing thermal flow sensors capable of monitoring flows in approximately the nL/min ranges have various disadvantages. One class of thermal flow sensors tightly wrap a fine coil of resistance wire around the tube to measure temperature. This design can be difficult to manufacture because the fine coil must be precisely placed along the tube and consistently make contact with the tube. In addition, due to its large thermal mass, a lengthy coil and therefore a bulky coil is required to overcome its slow response to flow rate changes.
Another class of thermal sensors bonds an extremely small micro-fabricated device that contains two temperature sensors and heating element on one chip to a tube. Although the microfabricated type of flow sensor is sensitive and has a fast time response, it is costly to manufacture in small quantities due to the microfabrication process.